Glioblastoma (GBM), the most common type of malignant brain cancer, is uniformly fatal despite ongoing research into the development of novel therapeutics. One reason for the high lethality of GBM is the presence of a self-renewing population of cells that is resistant to chemo- and radiation therapy, termed cancer stem cells (CSCs). Although the cancer stem cell hypothesis remains controversial, we and others have shown that directly targeting this population of cells decreases tumor growth and initiation and sensitizes tumors to current clinical therapies. Cellular interactions within the CSC compartment and between CSCs and non-CSCs help maintain the balance between CSC self-renewal and differentiation. Direct cell interactions may also allow cells to rapidly adapt in response to tumo growth and the presence of chemotherapeutics. Gap junctions, one type of cell-cell contact mechanism, are composed of connexin subunits that form connexon channels, which allow the transport of small molecules from cell to cell. The translational goal of this project is to conduc mechanistic studies into the role of cell-cell interactions in the progression of GBM. We hypothesize that cell type-specific communication is controlled by a balance of connexin subunits and that disrupting this balance attenuates GBM progression. We will interrogate this hypothesis by investigating the following aims: 1) that the balance between connexin subunits exerts differential effects on CSCs, non-CSCs, and normal neural cells; 2) that Cx46 contributes to CSC maintenance; and 3) that in vivo targeting of connexin subunits attenuates GBM progression. The long-term goal of this project is to translate the information gained about direct cell-cell communication in GBM to inhibition strategies useful as clinical therapies.